Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787.

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

Efficacy of heel lifts for lower limb musculoskeletal conditions: A systematic review.

INTRODUCTION: The objective of this systematic review is to determine the benefits and harms of heel lifts to any comparator for lower limb musculoskeletal conditions. METHODS: Ovid MEDLINE, Ovid AMED, Ovid EMCARE, CINAHL Plus and SPORTDiscus were searched from inception to the end of May 2024. Randomised, quasi-randomised or non-randomised trials comparing heel lifts to any other intervention or no-treatment were eligible for inclusion. Data was extracted for the outcomes of pain, disability/function, participation, participant rating of overall condition, quality of life, composite measures and adverse events. Two authors independently assessed risk of bias and certainty of evidence using the GRADE approach at the primary time point 12 weeks (or next closest). RESULTS: Eight trials (n = 903), investigating mid-portion Achilles tendinopathy, calcaneal apophysitis and plantar heel pain were included. Heel lifts were compared to exercise, ultrasound, cryotherapy orthotics, stretching, footwear, activity modification, felt pads and analgesic medication. No outcome was at low risk of bias and few effects (2 out of 47) were clinically important. Low-certainty evidence (1 trial, n = 199) indicates improved pain relief (55.7 points [95% CI: 50.3-61.1], on a 100 mm visual analogue scale) with custom orthotics compared to heel lifts at 12 weeks for calcaneal apophysitis. Very low-certainty evidence (1 trial, n = 62) indicates improved pain and function with heel lifts over indomethacin (35.5 points [95% CI: 21.1-49.9], Foot Function Index) at 12 months for plantar heel pain. CONCLUSIONS: Few trials have assessed the benefits and harms of heel lifts for lower limb musculoskeletal conditions. Only two outcomes out of 47 showed clinically meaningful between group differences. However, due to very low to low certainty evidence we are unable to be confident in the results and the true effect may be substantially different. REGISTRATION: PROSPERO registration number CRD42022309644.

Demographic and mental health profile of youth in a gender service: An African case series.

Background: Despite a massive global increase in research on gender-diverse youth, there have been no studies in Africa on gender-diverse children and adolescents presenting to health services. Aim: This study aimed to present the first African findings of the demographic and mental health profile of youth who have presented at a gender service in South Africa. Setting: A specialist mental health outpatient service, consisting of psychiatry, psychology and nursing input, for gender-diverse child and adolescent patients in the Western Cape. Methods: All consenting youth seen at a gender service, consisting of psychiatry, psychology and nursing input, in state and by the same clinician in private practice between January 2012 and May 2019 were participants of a retrospective, sequential case series study. Data of interest, including gender identity and sexuality, mental health history and social information, were extracted from the psychiatry files of participants. Results: Thirty-nine participants were part of the registry and qualified for the study: 72% self-identified as white, 15% as coloured and 13% as black African. The rate of co-occurring psychopathology was high (64%) and included high rates of autism, particularly in trans males (26%), suicidal ideation in 31% and a history of suicide attempt(s) in 10%. Conclusions: This first study describing gender-diverse youth seeking support relating to their gender identity in Africa showed they had remarkable similarities to those studied internationally. Contribution: Establishing that transgender youth of all major racial groups in the province with similar demographic profiles to other parts of the world are presenting to services in South Africa and in need of mental health support and interventions.

Efficacy of heel lifts for mid-portion Achilles tendinopathy (the LIFT trial): study protocol for a randomised controlled trial.

BACKGROUND: Mid-portion Achilles tendinopathy is a common condition, characterised by localised Achilles tendon load-related pain and dysfunction. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. Heel lifts have also been advocated as a treatment for Achilles tendinopathy, but the efficacy and mechanism of action of this intervention is unclear. This proposal describes a randomised controlled trial comparing the effectiveness of heel lifts versus sham heel lifts for reducing pain associated with mid-portion Achilles tendinopathy, with an embedded biomechanical analysis. METHODS: One hundred and eight men and women aged 18 to 65 years with mid-portion Achilles tendinopathy (who satisfy the inclusion and exclusion criteria) will be recruited. Participants will be randomised, using the website Sealed Envelope, to either a control group (sham heel lifts) or an experimental group (heel lifts). Both groups will be provided with education regarding acceptable pain levels to ensure all participants receive some form of treatment. The participants will be instructed to use their allocated intervention for at least 8 h every day for 12 weeks. The primary outcome measure will be pain intensity (numerical rating scale) at its worst over the previous week. The secondary outcome measures will be additional measures of Achilles tendon pain and disability, participant-perceived global ratings of change, function, level of physical activity and health-related quality of life. Data will be collected at baseline and the primary endpoint (week 12). Data will be analysed using the intention-to-treat principle. In addition, the acute kinetic and kinematic effects of the interventions will be examined at baseline in a subpopulation of the participants (n = 40) while walking and running using three-dimensional motion analysis. DISCUSSION: The LIFT trial (efficacy of heeL lIfts For mid-portion Achilles Tendinopathy) will be the first randomised trial to compare the efficacy of heel lifts to a sham intervention in reducing pain and disability in people with Achilles tendinopathy. The biomechanical analysis will provide useful insights into the mechanism of action of heel lifts. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12623000627651 . Registered 7 June 2023.

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

First Phase Development of a Patient-reported Outcome Measure for Midface Oncology.

Background: Facial cancer surgery involving the midface (comprising the lower eyelids, nose, cheeks, and upper lip) can have debilitating life-changing functional, social, and psychological impacts on the patient. Midface symptoms are inadequately captured by existing patient-reported outcome measures (PROMs). PROMs are increasingly used for individual patient care, quality improvement, and standardized reporting of treatment outcomes. This study aimed to present our findings from the first phase of the development of a midface, specifically periocular and nasal, PROM. Methods: After international guidance for PROM development, the first phase comprised identification of salient issues and item generation. Fifteen patients who had midface surgery and 10 clinicians from various specialties with more than 5 years' experience treating these patients were recruited. Semi-structured interviews explored aesthetic, functional, social, and psychological outcomes, with specific attention to deficiencies in current PROMs. Thematic analysis was used to develop an item pool, and group interviews with clinicians were carried out to create and refine PROM scales. Results: Qualitative data from patient interviews were grouped into aesthetic, functional, and psychosocial domains for the eyelids and nose. Ninety-nine draft items were generated across these domains. Following focus group discussions, the final version of the midface-specific PROM contained 31 items (13 eye-specific, 10-nose-specific, eight general midface items). Conclusions: This midface-specific PROM is valuable in assessing and comparing patient-reported outcomes in those who have undergone complex resection and reconstruction of the midface. This PROM is currently undergoing field testing.

Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.

Assessing the effects of foot strike patterns and shoe types on the control of leg length and orientation in running.

This research investigates the stabilization of leg length and orientation during the landing phase of running, examining the effects of different footwear and foot strike patterns. Analyzing kinematic data from twenty male long-distance runners, both rearfoot and forefoot strikers, we utilized the Uncontrolled Manifold approach to assess stability. Findings reveal that both leg length and orientation are indeed stabilized during landing, challenging the hypothesis that rearfoot strikers exhibit less variance in deviations than forefoot strikers, and that increased footwear assistance would reduce these deviations. Surprisingly, footwear with a lower minimalist index enhanced post-landing stability, suggesting that cushioning contributes to both force dissipation and leg length stability. The study indicates that both foot strike patterns are capable of effectively reducing task-relevant variance, with no inherent restriction on flexibility for rearfoot strikers. However, there is an indication of potential reliance on footwear for stability. These insights advance our understanding of the biomechanics of running, highlighting the role of footwear in stabilizing leg length and orientation, which has significant implications for running efficiency and injury prevention.

Overground gait adaptability in older adults with type 2 diabetes in response to virtual targets and physical obstacles.

BACKGROUND: To step over an unexpected obstacle, individuals adapt gait; they adjust step length in the anterior-posterior direction prior to the obstacle and minimum toe clearance height in the vertical direction during obstacle avoidance. Inability to adapt gait may lead to falls in older adults with diabetes as the results of the effects of diabetes on the sensory-motor control system. Therefore, this study aimed to investigate gait adaptability in older adults with diabetes. RESEARCH QUESTION: Would diabetes impair gait adaptability and increase sagittal foot adjustment errors? METHODS: Three cohorts of 16 people were recruited: young adults (Group I), healthy older adults (Group II), and older adults with diabetes (Group III). Participants walked in baseline at their comfortable speeds. They then walked and responded to what was presented in gait adaptability tests, which included 40 trials with four random conditions: step shortening, step lengthening, obstacle avoiding, and walking through. Virtual step length targets were 40% of the baseline step length longer or shorter than the mean baseline step length; the actual obstacle was a 5-cm height across the walkway. A Vicon three-dimensional motion capture system and four A.M.T.I force plates were used to quantify spatiotemporal parameters of a gait cycle and sagittal foot adjustment errors (differences between desired and actual responses). Analyses of variance (ANOVA) repeated measured tests were used to investigate group and condition effects on dependent gait parameters at a significance level of 0.05. RESULTS: Statistical analyses of Group I (n = 16), Group II (n = 14) and Group III (n = 13) revealed that gait parameters did not differ between groups in baseline. However, they were significantly different in adaptability tests. Group III significantly increased their stance and double support times in adaptability tests, but these adaptations did not reduce their sagittal foot adjustment errors. They had the greatest step length errors and lowest toe-obstacle clearance, which could cause them to touch the obstacle more. SIGNIFICANCE: The presented gait adaptability tests may serve as entry tests for falls prevention programs.

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

PURPOSE: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). EXPERIMENTAL DESIGN: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. RESULTS: VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. CONCLUSIONS: By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.

Effects of diabetes mellitus on step length and minimum toe clearance adaptation.

BACKGROUND: Adaptive gait involves the ability to adjust the leading foot in response to the requirement of dynamic environments during walking. Accurate adjustments of the minimum toe clearance (MTC) height and step length can prevent older people from falling when walking and responding to hazards. Although older people with diabetes fall more frequently than healthy older adults, no previous studies have quantified their adaptive gait abilities. This study aimed to investigate the effects of diabetes mellitus on step length and MTC height adjustments using a non-immersive virtual-reality system. METHODS: Sixteen young adults (26 ± 5 years, 7 females), 16 healthy older adults (68 ± 5 years, 6 females), and 16 older adults with diabetes (70 ± 5 years, 6 females) completed adaptability tests while walking on a treadmill. A computer system visualised a continuous real-time signal of absolute step length and MTC on a monitor. Each person responded to four discrete participant-specific step length and MTC visual targets that were presented on the same signal. Tasks were to match the peaks of interest on each signal to presented targets. Targets were 10% longer or shorter than the mean baseline step length, and 2.5 cm, and 3.5 cm higher than the mean baseline MTC. When a target was displayed, it remained unchanged for 10 consecutive foot displacement adaptation attempts. Then, the target was removed and a new target or the same target was present after 10 consecutive steps and remained for 10 steps. Each target was randomly presented three times (3 × 10). Step length and MTC height adjustments in response to targets were measured and compared among groups. RESULTS: Mean preferred walking speeds were not different among groups significantly when no targets were presented on the monitor in baseline walking. However, when participants walked on a treadmill while attempting to match step lengths or MTC heights to displayed targets on the monitor, the group with diabetes had reduced step length and MTC adjustments compared with other groups significantly. They showed greater errors (differences between their step lengths/MTC heights and presented targets) on the monitor. CONCLUSIONS: This study quantified reduced abilities for older individuals with diabetes to adjust both step length and MTC in response to stimuli compared to healthy older counterparts. Reduced step length and MTC height adjustments can increase falls in at risk populations. The presented virtual-reality system has merits for assessing and training step and MTC adaptation.

Repurposing the Ordering of Routine Laboratory Tests in Hospitalised Medical Patients (RePORT): results of a cluster randomised stepped-wedge quality improvement study.

BACKGROUND: Low-value use of laboratory tests is a global challenge. Our objective was to evaluate an intervention bundle to reduce repetitive use of routine laboratory testing in hospitalised patients. METHODS: We used a stepped-wedge design to implement an intervention bundle across eight medical units. Our intervention included educational tools and social comparison reports followed by peer-facilitated report discussion sessions. The study spanned October 2020-June 2021, divided into control, feasibility testing, intervention and a follow-up period. The primary outcomes were the number and costs of routine laboratory tests ordered per patient-day. We used generalised linear mixed models, and analyses were by intention to treat. RESULTS: We included a total of 125 854 patient-days. Patient groups were similar in age, sex, Charlson Comorbidity Index and length of stay during the control, intervention and follow-up periods. From the control to the follow-up period, there was a 14% (incidence rate ratio (IRR)=0.86, 95% CI 0.79 to 0.92) overall reduction in ordering of routine tests with the intervention, along with a 14% (ß coefficient=-0.14, 95% CI -0.07 to -0.21) reduction in costs of routine testing. This amounted to a total cost savings of $C1.15 per patient-day. There was also a 15% (IRR=0.85, 95% CI 0.79, 0.92) reduction in ordering of all common tests with the intervention and a 20% (IRR=1.20, 95% CI 1.10 to 1.30) increase in routine test-free patient-days. No worsening was noted in patient safety endpoints with the intervention. CONCLUSIONS: A multifaceted intervention bundle using education and facilitated multilevel social comparison was associated with a safe and effective reduction in use of routine daily laboratory testing in hospitals. Further research is needed to understand how system-level interventions may increase this effect and which intervention elements are necessary to sustain results.

Movement Foundations. The perceived impact of a digital rehabilitation tool for returning to fitness following a period of illness, including COVID-19 infection: a qualitative study.

Digital interventions can increase physical activity (PA) levels in adults. However, the COVID-19 pandemic highlighted the complexities faced when guiding people to start or return to PA following illness or inactivity. A digital tool, Movement Foundations, was developed to provide remote guidance on building strength and capacity across functional movement patterns, with graduated progression based on user responses and input. This qualitative study aimed to explore the perceived impacts of using the tool. Nine participants aged over 35 years from the healthcare and academic healthcare sectors were recruited to use it and were subsequently interviewed. Thematic analysis identified three themes falling under the overarching concept of 'Capability, Opportunity and Motivation-Behaviour (COM-B) Plus', encompassing: skills and capacity for movement; opportunities, motivations and barriers for movement; and a personalised, safe space in which to develop. Participants felt that the digital tool increased their capacity and confidence in movement and positively impacted their daily activities. External factors such as illness and stress clouded perceptions of the impacts of PA. Time, work pressures and needing equipment were still considered significant barriers to PA. Still, participants appreciated the flexibility and non-prescriptive nature of the tool and felt that it helped movement to become opportunistic and habitual. Increased capacity for PA and feeling the subsequent physical and mental effects positively influenced motivation. Structure and guidance, with graduated progress, were seen as protective. Guided self-reflection helped participants understand their capacity and limitations with regard to movement and promoted motivation. Although acquiring technical skills to guide movement may be important for those recovering from illness, participants found that a structure promoting individualised guidance, graduated progression and guided self-reflection were important motivational factors for continuing use. Digital interventions should consider these aspects when seeking to promote habitual PA.

Influence Maximization in Multiagent Systems by a Graph Embedding Method: Dealing With Probabilistically Unstable Links.

This article is concerned with the influence maximization (IM) problem under a network with probabilistically unstable links (PULs) via graph embedding for multiagent systems (MASs). First, two diffusion models, the unstable-link independent cascade (UIC) model and the unstable-link linear threshold (ULT) model, are designed for the IM problem under the network with PULs. Second, the MAS model for the IM problem with PULs is established and a series of interaction rules among agents are built for the MAS model. Third, the similarity of the unstable structure of the nodes is defined and a novel graph embedding method, termed the unstable-similarity2vec (US2vec) approach, is proposed to tackle the IM problem under the network with PULs. According to the embedding results of the US2vec approach, the seed set is figured out by the developed algorithm. Finally, extensive experiments are conducted to: 1) verify the validity of the proposed model and the developed algorithms and 2) illustrate the optimal solution for IM under different scenarios with PULs.

Radiotherapy for nasopharyngeal carcinoma: Effect on the eye 10 years later: A case report.

A patient who had previously received radiotherapy for a nasopharyngeal carcinoma was rightfully discharged from otorhinolaryngology and oncology once treatment was completed. After 10 years, the patient presented with visual loss in one eye and was found to have radiation retinopathy. This case highlights the importance of recognising the effects that radiation administered to structures near the eye can have on vision. The latency of this case demonstrates the need for routine eye tests in patients who have undergone radiotherapy near the orbit. Prompt recognition and referral to ophthalmologists is necessary for all suspected cases to best manage visual loss.

Safety and effectiveness of the fluocinolone acetonide intravitreal implant (ILUVIEN): 3-year results from the European IRISS registry study.

BACKGROUND: The ILUVIEN Registry Safety Study was a multicentre, open-label, non-randomised, observational, phase 4 study designed to assess the safety and effectiveness of the fluocinolone acetonide (FAc) implant in all indications in real-world practices in Europe. METHODS: The study included data collected prospectively and retrospectively. Patients receiving FAc implants between 2013 and 2017 were included and monitored until the last patient reached ≥3 years of follow-up. Mean intraocular pressure (IOP) data over the course of the study, along with IOP events, use of IOP-lowering therapy, mean change in visual acuity (VA) and information on supplemental therapy use were analysed post-FAc implantation. RESULTS: Six hundred and ninety-five eyes from 556 patients, with a mean±SD follow-up of 1150.5±357.36 days, were treated with a FAc implant. 96.7% of eyes had chronic diabetic macular oedema (cDMO). IOP lowering was achieved in 34.5% of eyes using topical agents and 4.3% by surgery. Seventy-three eyes (64.6% of 113 phakic) required cataract surgery during follow-up. Mean VA increased from a baseline of 52.2 letters to 57.1 letters at month 36, with improvement observed up to month 48. Supplementary therapies were given in 43.7% of eyes. When classified by length of cDMO less than or greater than the median duration those with a shorter history experienced greater VA gains than those with a longer history. CONCLUSION: This study confirms the favourable, long-term benefit-to-risk profile of the FAc implant in eyes with cDMO, with an additional benefit in patients when this therapy is administered earlier.

Non-specific binding of compounds in in vitro metabolism assays: a comparison of microsomal and hepatocyte binding in different species and an assessment of the accuracy of prediction models.

Non-specific binding in in vitro metabolism systems leads to an underestimation of the true intrinsic metabolic clearance of compounds being studied. Therefore in vitro binding needs to be accounted for when extrapolating in vitro data to predict the in vivo metabolic clearance of a compound. While techniques exist for experimentally determining the fraction of a compound unbound in in vitro metabolism systems, early in drug discovery programmes computational approaches are often used to estimate the binding in the in vitro system.Experimental fraction unbound data (n = 60) were generated in liver microsomes (fumic) from five commonly used pre-clinical species (rat, mouse, dog, minipig, monkey) and humans. Unbound fraction in incubations with mouse, rat or human hepatocytes was determined for the same 60 compounds. These data were analysed to determine the relationship between experimentally determined binding in the different matrices and across different species. In hepatocytes there was a good correlation between fraction unbound in human and rat (r2=0.86) or mouse (r2=0.82) hepatocytes. Similar correlations were observed between binding in human liver microsomes and microsomes from rat, mouse, dog, Göttingen minipig or monkey liver microsomes (r2 of >0.89, n = 51 - 52 measurements in different species). Physicochemical parameters (logP, pKa and logD) were predicted for all evaluated compounds. In addition, logP and/or logD were measured for a subset of compounds.Binding to human hepatocytes predicted using 5 different methods was compared to the measured data for a set of 59 compounds. The best methods evaluated used measured microsomal binding in human liver microsomes to predict hepatocyte binding. The collated physicochemical data were used to predict the human fumic using four different in silico models for a set of 53-60 compounds. The correlation (r2) and root mean square error between predicted and observed microsomal binding was 0.69 & 0.20, 0.47 & 0.23, 0.56 & 0.21 and 0.54 & 0.26 for the Turner-Simcyp, Austin, Hallifax-Houston and Poulin models, respectively. These analyses were extended to include measured literature values for binding in human liver microsomes for a larger set of compounds (n=697). For the larger dataset of compounds, microsomal binding was well predicted for neutral compounds (r2=0.67 - 0.70) using the Poulin, Austin, or Turner-Simcyp methods but not for acidic or basic compounds (r2<0.5) using any of the models. While the lipophilicity-based models can be used, the in vitro binding should be measured for compounds where more certainty is needed, using appropriately calibrated assays and possibly established weak, moderate, and strong binders as reference compounds to allow comparison across databases.

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.

CALMS: Modelling the long-term health and economic impact of Covid-19 using agent-based simulation.

We present our agent-based CoronAvirus Lifelong Modelling and Simulation (CALMS) model that aspires to predict the lifelong impacts of Covid-19 on the health and economy of a population. CALMS considers individual characteristics as well as comorbidities in calculating the risk of infection and severe disease. We conduct two sets of experiments aiming at demonstrating the validity and capabilities of CALMS. We run simulations retrospectively and validate the model outputs against hospitalisations, ICU admissions and fatalities in a UK population for the period between March and September 2020. We then run simulations for the lifetime of the cohort applying a variety of targeted intervention strategies and compare their effectiveness against the baseline scenario where no intervention is applied. Four scenarios are simulated with targeted vaccination programmes and periodic lockdowns. Vaccinations are targeted first at individuals based on their age and second at vulnerable individuals based on their health status. Periodic lockdowns, triggered by hospitalisations, are tested with and without vaccination programme in place. Our results demonstrate that periodic lockdowns achieve reductions in hospitalisations, ICU admissions and fatalities of 6-8% compared to the baseline scenario, with an associated intervention cost of £173 million per 1,000 people and targeted vaccination programmes achieve reductions in hospitalisations, ICU admissions and fatalities of 89-90%, compared to the baseline scenario, with an associated intervention cost of £51,924 per 1,000 people. We conclude that periodic lockdowns alone are ineffective at reducing health-related outputs over the long-term and that vaccination programmes which target only the clinically vulnerable are sufficient in providing healthcare protection for the population as a whole.